Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 302, Issue 9, Pages G948-G957Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00359.2011
Keywords
liver; cytokine; gene expression; signal pathway
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-50574]
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Li T, Shi Z, Rockey DC. Preproendothelin-1 expression is negatively regulated by IFN gamma during hepatic stellate cell activation. Am J Physiol Gastrointest Liver Physiol 302: G948-G957, 2012. First published February 2, 2012; doi:10.1152/ajpgi.00359.2011.-Endothelin-1(ET-1), a powerful vasoconstrictor peptide, is produced by activated hepatic stellate cells (HSC) and promotes cell proliferation, fibrogenesis, and contraction, the latter of which has been thought to be mechanistically linked to portal hypertension in cirrhosis. Interferon-gamma (IFN gamma), a Th1 cytokine produced by T cells, inhibits stellate cell proliferation, fibrogenesis, and muscle-specific gene expression. Whether IFN gamma-induced inhibitory effects are linked to regulation of ET-1 expression in activated stellate cells remains unknown. Here we examined IFN gamma's effects on preproET-1 mRNA expression and the signaling pathways underlying this process. We demonstrated that preproET-1 mRNA expression in HSCs was prominently increased during cell culture-induced activation; IFN gamma significantly inhibited both preproET-1 mRNA expression and ET-1 peptide production. Similar results were found in an in vivo model of liver injury and intraperitoneal administration of IFN gamma. PreproET-1 promoter analysis revealed that IFN gamma-induced inhibition of preproET-1 mRNA expression was closely linked to the AP-1 and Smad3 signaling pathways. Furthermore, IFN gamma reduced JNK phosphorylation, which tightly was associated with decreased phosphorylation of downstream factors c-Jun and Smad3 and decreased binding activity of c-Jun and Smad3 in the preprpET-1 promoter. Importantly, IFN gamma reduced both c-Jun mRNA and protein levels. Given the important role of ET-1 in wound healing, our results suggest a novel negative signaling network by which IFN gamma inhibits preproET-1 expression, highlighting one potential molecular mechanism for IFN gamma-induced host immunomodulation of liver fibrogenesis.
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